Heart 

Histological sections show an extracellular deposition of a homogenous, amorphous, and pale eosinophilic material in the myocardial interstitium forming nodules and trapping myocytes. Small cracks can be appreciated within the deposited material. Congo red stain imparts a salmon red appearance and shows yellow-green birefringence under polarized light. The light microscopic findings, coupled with a positive Congo red stain and identification of a TTR V122I variant, support the diagnosis of cardiac hereditary transthyretin amyloidosis.  

Cardiac amyloidosis is a term used to describe a variety of inherited and acquired restrictive cardiomyopathies characterized by the extracellular deposition of misfolded insoluble protein fibrils. Involvement of the myocardium confers a waxy appearance, and often the changes are more evident in the ventricles with a predilection to affect the posterobasal septum. This leads to an increased septum-to-free ventricular wall ratio that can grossly mimic hypertrophic cardiomyopathy. Amyloid atrial involvement is less prominent. Deposits in the endocardium (primarily left atrium) and valves can cause a gritty or sandpaper-like texture to the inner surfaces, while irregular rough white patches on the outside surface are appreciated with epicardial involvement.  

Under the microscope, the amyloid deposits can be seen in a pericellular pattern around individual myocytes, in a nodular pattern, or both. The epicardial coronary arteries are usually involved; however, this pattern of deposition does not contribute to obstructive ischemic coronary disease. On the other hand, in the myocardium obstructive vascular deposits may be seen, which can be associated with ischemic heart disease. The histopathologic deposition patterns of cardiac amyloidosis are not type specific; however, frequent vascular involvement and diffuse pericellular deposits are more commonly observed in light chain (AL)-type amyloidosis.  

The amyloid fibril is designated protein A and is followed by a suffix that abbreviates the precursor protein name (eg, AL = Amyloid fibril with Light chain immunoglobulin as precursor protein); on the other hand, the term amyloidosis refers to the disease caused by deposition of amyloid fibrils. More than 30 amyloid fibril proteins in humans have been described and 11 can involve the heart. The two most common forms of clinically significant cardiac amyloidosis are caused by deposition of AL-type and transthyretin (ATTR)-type amyloid. AL-type amyloid accounts for approximately 80% of cases and is invariably associated with plasma cell or other plasmacytic B-cell neoplasms.

ATTR amyloidosis can occur in acquired and hereditary forms. The former, also known as wild-type ATTR amyloidosis, is more common than the hereditary form and is an underrecognized cause of heart failure. Wild-type ATTR amyloidosis is also referred to as senile systemic amyloidosis and has been reported to predominately affect men older than 60 to 70 years old. Hereditary ATTR amyloidosis is an autosomal dominant trait with variable penetrance, and multiple single-nucleotide TTR gene mutations have been described. The TTR V122I variant is one of most common mutations and increases the risk of developing cardiac amyloidosis. The amyloidogenic V122I variant is emerging as a hitherto underrecognized cause of cardiomyopathy in individuals of African and Hispanic ancestry. As the awareness of ATTR amyloidosis increases, the demographics of this disease will be better defined.

The diagnostic evaluation of a patient with suspected cardiac amyloidosis initially consists of testing for monoclonal light chains, including serum and urine electrophoresis with immunofixation and serum free light chain ratio, and a bone scintigraphy scan with 99mTechnetium-pyrophosphate (99mTc-PYP). The latter is fairly specific for ATTR-type amyloid. In selective situations, endomyocardial biopsy is necessary to establish the diagnosis and allow for amyloid subtyping by mass spectrometry. If the diagnosis of ATTR amyloidosis is established, genetic counseling and testing for TTR gene variants is recommended to define hereditary versus wild-type disease.  

Cardiac hemochromatosis, also known as primary iron-overload cardiomyopathy, can be a clinical component of hereditary hemochromatosis (HH). HH is a systemic autosomal recessive disorder in which there is increased intestinal iron absorption leading to total-body iron overload. C282Y mutation of the HFE gene is the most common alteration in HH. Cardiac involvement in HH may be assessed by MRI or endomyocardial biopsy. Cardiac hemochromatosis is histologically characterized by a golden-brown granular pigment, which can be highlighted by iron stain, within myocytes, often showing a perinuclear pattern.  

Cardiac light chain deposition disease, also known as cardiac nonamyloidotic immunoglobin deposition disease (CIDD), is a rare disorder in which the protein seen deposited in tissue is monoclonal light chains. In contrast to AL-type amyloidosis, the deposition of light chains in CIDD is Congo Red negative, and electron microscopy shows nonfibrillar and granular electron-dense deposits. Endomyocardial biopsies usually show normal myocytes and vasculature architecture. Immunofluorescence can be used to identify the interstitial deposits of light chains.

Fabry disease-related cardiomyopathy occurs in the setting of an X-linked storage disease caused by mutations in GLA, a gene responsible for encoding the lysosomal enzyme α-galactosidase A. GLA mutations lead to progressive cellular accumulation of globotriaosylceramide (GL-3 or Gb3) in lysosomes in different tissues. In the heart, the GL-3/Gb3 deposition affects the valves, myocytes, nerves, and coronary arteries. Histologically, the myocardium shows myocyte hypertrophy with extensive cytoplasmic vacuolization and variable degrees of interstitial fibrosis. The cytoplasmic vacuolar change is also present in the vascular smooth muscle cells. Electron microscopy of the myocardium characteristically show myelin figures or zebra bodies, which represent intra-lysosomal aggregates of concentric or parallel lamellae with alternating dense and light bands.

Hypertrophic cardiomyopathy (HCM) is most often an inherited cardiovascular disorder characterized by left ventricular hypertrophy without chamber dilatation unexplained by the loading conditions. The myocardium involvement is usually asymmetric and predominantly affects the basal interventricular septum. HCM shows an autosomal dominant pattern of inheritance, and mutations in multiple genes encoding sarcomeric and associated myofibrillar proteins have been described. Approximately half of HCM patients harbor mutations in either β-myosin heavy chain (MYH7) or myosin binding protein C (MYBPC3). On gross examination, there is marked septal thickening that results in a septum-to-free ventricle wall ratio of ≥1.3. Microscopically, HCM exhibits myocyte disarray with cartwheel or storiform patterns and myocyte hypertrophy with bizarre nuclei, nuclear enlargement, pleomorphism, and hyperchromasia. Increased interstitial fibrosis and replacement-type myocardial fibrosis are common features of HCM. 

1. Which of the following is true regarding cardiac amyloidosis?  
    
   1. A nodular pattern of amyloid deposition is diagnostic of ATTR-type amyloid.  
   2. ATTR-type amyloid deposition is restricted to the coronary arteries.
   3. Cardiac light chain deposition disease is a synonym for cardiac AL-type amyloid.
   4. It can grossly mimic hypertrophic cardiomyopathy.  
   5. It results from extracellular deposition of globotriaosylceramide.  
       
2. Which of the following is true regarding ATTR-type amyloidosis? 
    
   1. All forms of ATTR are associated with an underlying plasma cell neoplasm.
   2. Congo red stain is the best method to sub-type ATTR-type amyloid.
   3. It is the most common cause of clinically significant cardiac amyloidosis.
   4. The TTR V122I variant is protective for the development of cardiac amyloidosis.
   5. Wild-type ATTR is more common than hereditary ATTR.  
3. Which of the following is the precursor protein for the amyloid fibril in senile systemic amyloidosis? 
    
   1. Atrial natriuretic factor  
   2. β2-microglobulin
   3. Immunoglobulin light chain
   4. Serum amyloid A
   5. Transthyretin, wild type   

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2. Damrauer SM, Chaudhary K, Cho JH, et al. Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. JAMA. 2019;322(22):2191-2202.  
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5. Maleszewski JJ. Cardiac amyloidosis: pathology, nomenclature, and typing. Cardiovasc Pathol. 2015;24(6):343-350.  
6. Sekijima Y. Hereditary Transthyretin Amyloidosis. 2001[updated 2021]. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.  
7. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213.  
8. Toor AA, Ramdane BA, Joseph J, et al. Cardiac nonamyloidotic immunoglobulin deposition disease. Mod Pathol. 2006;19(2):233-237. 

1. It can grossly mimic hypertrophic cardiomyopathy (d)
2. Wild-type ATTR is more common than hereditary ATTR. (e)
3. Transthyretin, wild type (e.)